The clinical objective in treatment of peptic ulcer disease is to decrease gastric acid secretion, based on the principle "no acid, no ulcer." Traditional peptic ulcer disease therapy involves control of diet and the use of antacids and anticholinergics.
There is evidence indicating that histamine may be the final common pathway for stimulation of gastric secretion. This effect of histamine is mediated via H.sub.2 receptors and is not inhibited by the classical antihistamines, which are H.sub.1 -receptor blockers. A number of specific H.sub.2 -receptor blocking agents (H.sub.2 -receptor antagonists) are now known. These compounds inhibit basal acid secretion, as well as secretion by other known gastric acid stimulants, and are useful in the treatment of peptic ulcers.
Burimamide (IIa) was the first clinically effective H.sub.2 -receptor antagonist. It inhibits gastric secretion in animals and man, but oral absorption is poor. ##STR2## Metiamide (IIb), a subsequently evaluated H.sub.2 antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (IIc) is as effective an H.sub.2 antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug. The half-life of cimetidine is relatively short, thereby necessitating a therapeutic regimen of multi daily doses of 200-300 mg. tablets. There is thus a need for anti-ulcer agents which are longer acting and/or more potent than cimetidine.
Reviews on the development of H.sub.2 antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13 (1976), and in references cited therein. Relevant patents are as follows:
Belgian Pat. No. 841,814 (Farmdoc 90568X) discloses inhibitors of histamine-stimulated gastric secretion having the formula ##STR3## in which HET is one of eight named heterocyclic rings (all of which contain at least one nitrogen, thereby excluding furyl) which may be substituted by (lower)-alkyl, hydroxy, amino or halogen, Z is sulfur or CH.sub.2, X is S, CHNO.sub.2, NCN or NH, Y is NH.sub.2, (lower)alkylamino, di(lower)alkylamino, (lower)alkoxy, phenylethyl, imidazolylethyl, allyl, trifluoroethyl or (CH.sub.2).sub.n R in which n is 1-12 and R is OH, (lower)alkoxy, NH.sub.2 or (lower)-alkylamino; provided that, when X is NH, Y is trifluoroethyl or (CH.sub.2).sub.n R; and when X is NCN, Y may not be amino or alkylamino.
Belgian Pat. No. 857,388 discloses histamine H.sub.2 -receptor inhibitors of the formula ##STR4## in which R.sup.1 and R.sup.2 are the same or different and are hydrogen, (lower)alkyl, cycloalkyl, (lower)alkenyl, aralkyl or a (lower)alkyl group which is interrupted by an oxygen atom or by the group NR.sup.4 in which R.sup.4 is hydrogen or (lower)alkyl, or R.sup.1 and R.sup.2 together with the nitrogen atom form a heterocyclic ring optionally containing an oxygen atom or an NR.sup.4 group; A is (lower)alkylene; m is 2-4; n is 1 or 2, or can be zero when X is sulfur or CH.sub.2 ; X is oxygen, sulfur or CH.sub.2 ; Y is sulfur, oxygen, NR.sup.5 or CHR.sup.6 ; R.sup.5 is hydrogen, nitro, cyano, (lower)alkyl, aryl, alkylsulfonyl or arylsulfonyl; R.sup.6 is nitro, arylsulfonyl or alkylsulfonyl; and R.sup.3 is hydrogen, (lower)alkyl, (lower)-alkenyl or alkoxyalkyl.
U.S. Pat. No. 4,112,234 discloses histamine H.sub.2 -receptor inhibitors of the formula ##STR5## wherein R.sup.1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, and processes for the preparation thereof.